Previous studies of osteoclast-free animal models of inflammatory bone disease established the dogma that focal bone erosion in inflammatory arthritis is exclusively dependent on tartrate-resistant acid phosphatase (TRAP)-positive (+) osteoclasts. However, this paradigm may be reevaluated as a result of our studies of osteoclast-free cherubism mice. Cherubism is a genetic disorder in children characterized by expansile inflammatory bone destruction in maxilla and mandible due to gain-of-function mutations in SH3-domain binding protein 2 (SH3BP2). The mouse model of cherubism exhibits systemic bone destruction caused by increased osteoclastogenesis associated with macrophage inflammation. Therefore, we hypothesized that ablation of osteoclasts would rescue the inflammatory bone destruction in this model. Remarkably, considerable bone erosion was still present in FOS-deficient cherubism mice. This bone erosion occurred despite the fact that no TRAP+ cells were detected on bone surfaces. H&E staining showed inflammatory infiltrates on bone surface of FOS-deficient cherubism mice similar to that of FOS-sufficient cherubisn mice. Immunohistochemical staining with an antibody against F4/80 showed that erosion pits are primarily filled with macrophages. Expression levels of matrix metalloproteinases (MMPs) were increased in the inflamed joint tissue of FOS-deficient cherubism mice compared to FOS-deficient mice. In contrast, cathepsin K, a marker proteinase for osteoclasts, expression was not elevated. Consistent with these results, levels of serum ICTP, a marker of bone resorption produced by MMPs, were elevated in FOS-deficient cherubism mice compared to FOS-deficient mice, while serum CTX levels, another resorption marker by cathepsin K, were not increased. Finally, FOS-deficient cherubism macrophages cultured on dentine slice formed resorption pits. Collectively, our preliminary data suggest that FOS-deficient cherubism mice are a unique in vivo model of osteoclast- independent inflammatory bone resorption. The overall hypothesis for the proposed study is that macrophages can be converted to osteolytic cells in inflammatory conditions and that activation of the SH3BP2-SYK pathway that increases the expression of MMPs plays a critical role in conferring bone-resorbing capacity in macrophages. Specific aims are: Aim 1) Determine whether macrophages are responsible for bone erosion in FOS-deficient cherubism mice, Aim 2) Determine the role of MMPs in bone resorption by macrophages in FOS-deficient cherubism mice. Results will provide a unique opportunity to rethink what type of cells can resorb bone and whether and how activated macrophages can perform the pathological bone resorption, which will cause a paradigm shift in current therapeutic approaches to bone loss in cherubism as well as in common inflammatory arthritis such as rheumatoid arthritis. Furthermore, outcomes will provide insights into the pathology of bone loss in diseases where the mechanism of bone resorption cannot be fully explained by osteoclasts.